Apoptotic cell death induced by copper (II), manganese (II) and silver (I) complexes containing bridging dicarboxylate and 1,10-phenanthroline ligands: one of the multi-modes of anticancer activity?

Abstract

Cu(II), Mn(II) and Ag(I) complexes incorporating bridging dicarboxylate and 1,10-phenanthroline ligands have exhibited anti-cancer potential with significant in vitro and in vivo cytotoxic efficacies. Our study focuses on regulated cell death process of apoptosis as a mode of action of the anti-cancer activity by the complexes. Cytotoxicity screening of the complexes demonstrated all the metal-dicarboxylate-phenanthroline complexes exhibit superior activity compared to their non-phenanthroline containing precursors, in addition to cisplatin. The Cu(II) and Mn(II) complexes were shown to induce reactive oxygen species (ROS) but this was not observed for the Ag(I) analogues. Furthermore, apoptosis was found to be induced by all the metal-phenanthroline complexes to varying degrees contingent on the type of metal centre in the complex. Apoptotic gene expression analysis established the predominant activation of the intrinsic apoptotic pathway, with co-stimulation of the extrinsic pathway observed in some cases. The mechanistic data provided within this study highlights the multi-modal activity of the metal-phenanthroline complexes contingent on the type of metal present, warranting continued investigation of their biological modes of action beyond apoptosis induction.